Reproductive factors, menopausal hormone therapies and primary liver cancer risk: a systematic review and dose-response meta-analysis of observational studies.

BACKGROUND: A striking gender disparity in the incidence and outcome of primary liver cancer (PLC) has been well recognized. Mounting evidence from basic research suggests that hormonal factors may be involved in the gender disparity of PLC. Whether hormonal exposures in human subjects are associated with PLC risk is largely unknown. OBJECTIVE AND RATIONALE: Whether reproductive factors and use of menopausal hormone therapies (MHTs) in women are associated with PLC risk remains controversial. We conducted this study to clarify this issue. SEARCH METHODS: PubMed and EMBASE were searched to July, 2016 for studies published in English or Chinese. Observational studies (cohort, nested case-control and case-control) that provided risk estimates of reproductive factors, MHTs and PLC risk were eligible. The quality of included studies was determined based on the Newcastle-Ottawa quality assessment scale. Summary risk ratios (RRs) were calculated using a random-effects model. Dose-response analysis was conducted where possible. OUTCOMES: Fifteen peer-reviewed studies, involving 1795 PLC cases and 2 256 686 women, were included. Overall meta-analyses on parity and PLC risk did not find any significant associations; however, when restricting to studies with PLC cases ≥100, increasing parity was found to be significantly associated with a decreased risk of PLC [RR for the highest versus lowest parity 0.67, 95% CI 0.52, 0.88; RR for parous versus nulliparous 0.71, 95% CI 0.53, 0.94; RR per one live birth increase 0.93, 95% CI 0.88, 0.99]. A J-shaped relationship between parity and PLC risk was identified (Pnon-linearity < 0.01). Compared with never users, the pooled RRs of PLC were 0.60 (95% CI 0.37, 0.96) for ever users of MHT, 0.73 (95% CI 0.46, 1.17) for ever users of estrogen-only therapy (ET) and 0.67 (95% CI 0.45, 1.02) for ever users of estrogen-progestin therapy (EPT). The pooled RR of PLC for the oldest versus youngest category of menarcheal age was 0.50 (95% CI 0.32, 0.79). Oophorectomy was significantly associated with an increased risk of PLC (RR 2.23, 95% CI 1.46, 3.41). No significant association of age at first birth, and spontaneous or induced abortion with PLC risk was found. No meta-analysis was performed for the association of age at menopause, breastfeeding, hysterectomy, menopausal status and stillbirth with PLC risk owing to huge methodological heterogeneity and/or very limited studies. WIDER IMPLICATIONS: Parity is associated with PLC risk in a J-shaped dose-response pattern. Late age at menarche and ever use of MHT are associated with a reduced risk of PLC, whereas there is no association of ever use of ET and EPT, age at first birth, or spontaneous and induced abortion with PLC risk. Compared to women with no history of oophorectomy, those with a history of oophorectomy are at an increased risk of PLC. Our findings provide some epidemiological support for a role of hormonal exposures in the development of PLC in women. However, these findings should be interpreted with much caution because of the limited number of studies and potential biases, and need to be validated by studies with good design and large sample size.

HbA1c and Risks of All-Cause and Cause-Specific Death in Subjects without Known Diabetes: A Dose-Response Meta-Analysis of Prospective Cohort Studies.

Whether HbA1c levels are associated with mortality in subjects without known diabetes remains controversial. Moreover, the shape of the dose-response relationship on this topic is unclear. Therefore, a dose-response meta-analysis was conducted. PubMed and EMBASE were searched. Summary hazard ratios (HRs) were calculated using a random-effects model. Twelve studies were included. The summary HR per 1% increase in HbA1c level was 1.03 [95% confidence interval (CI) = 1.01-1.04] for all-cause mortality, 1.05 [95% CI = 1.02-1.07) for cardiovascular disease (CVD) mortality, and 1.02 (95% CI = 0.99-1.07) for cancer mortality. After excluding subjects with undiagnosed diabetes, the aforementioned associations remained significant for CVD mortality only. After further excluding subjects with prediabetes, all aforementioned associations presented non-significance. Evidence of a non-linear association between HbA1c and mortality from all causes, CVD and cancer was found (all Pnon-linearity < 0.05). The dose-response curves were relatively flat for HbA1c less than around 5.7%, and rose steeply thereafter. In conclusion, higher HbA1c level is associated with increased mortality from all causes and CVD among subjects without known diabetes. However, this association is driven by those with undiagnosed diabetes or prediabetes. The results regarding cancer mortality should be treated with caution due to limited studies.

Meta-analysis of oral contraceptive use and risks of all-cause and cause-specific death.

BACKGROUND: Whether ever use of oral contraceptives (OCs) is associated with mortality remains unclear. OBJECTIVES: To evaluate the association between ever use of OCs and mortality. SEARCH STRATEGY: On November 2, 2014, PubMed and Embase were searched for human studies, using the terms "contraceptive," "contraceptives," "death," and "mortality." SELECTION CRITERIA: Prospective cohort studies were included that provided risk estimates on OC use and mortality, and were reported in English or Chinese. DATA COLLECTION AND ANALYSIS: A random-effects model was used to pool data. Random-effects meta-regression was used to determine whether duration of OC use and time since last OC use were associated with mortality. MAIN RESULTS: Nine studies were included. Ever use of OCs was not associated with mortality from all causes (hazard ratio [HR] 0.94; 95% CI 0.87-1.02) or breast cancer (HR 1.00; 95% CI 0.95-1.06). Neither the duration of OC use nor the time since last OC use was associated with all-cause or breast cancer mortality. In an analysis of a small number of studies, ever users were at decreased risk of mortality from ovarian cancer (HR 0.58; 95% CI 0.35-0.94). CONCLUSIONS: There is no significant association between ever use of OCs and mortality from all causes or breast cancer.